Ophthalmic solution for absorbing ultraviolet radiation and method for absorbing ultraviolet radiation

ABSTRACT

An ophthalmic solution is provided. The ophthalmic solution includes an ultraviolet-A absorber and an ultraviolet-B absorber. The ophthalmic solution has a viscosity of between about 1 and 100 cps. The ophthalmic solution can be used to absorb ultraviolet radiation in the eye.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of U.S. application Ser. No. 13/489,561,filed on Jun. 6, 2012, pending, the entire disclosure of which is herebyexpressly incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to an ophthalmic solution including anultraviolet-A (UV-A) radiation absorber and an ultraviolet-B (UV-B)radiation absorber. The ophthalmic solution can be used to absorb UV-Aand UV-B radiation that comes in contact with an eye. The presentinvention also relates to a method for absorbing UV-A and UV-B radiationthat comes in contact with an eye.

BACKGROUND OF THE INVENTION

Exposure to ultraviolet radiation can cause aging of cells and mutagenicchanges to cells within the human body. Solar ultraviolet radiation ispresent in the rays of the sun, resulting in repeated and regularexposure by an eye to UV-A and UV-B radiation. The human ocular systemdoes not develop a tolerance to repeated ultraviolet exposure.

The acute effects of repeated and regular UV-A and UV-B radiationexposure include conjunctivitis and photokeratitis, a cornealinflammation reaction. Exposure to UV-A and UV-B radiation alsocontributes to early formation of cataracts, especially in persons withblonde hair and blue eyes living in sun belt zones of the United States.

It is important for the cornea to have an optically smooth surface forthe formation of a sharp visual image on the retina. Repeated exposureto ultraviolet radiation can result in the swelling or shrinking ofgroups of corneal epithelial cells. This can lead to visiblyrecognizable stippling or irregular mosaic granulation of the cornealsurface. With UV-A and UV-B exposure greater than the threshold forphotokeratitis, surface epithelial cells exhibit nuclear fragmentation,mid-epithelial cells exhibit vacuole formation, and basal cells exhibitinhibition of mitosis and clouding of the corneal stroma occurs.

A healthy cornea prevents exposure by the retina to ultravioletradiation. When the cornea is damaged or replaced, the eye becomesextremely sensitive to ultraviolet radiation and the retina is exposedto ultraviolet radiation.

The retina is a delicate nervous membrane upon which the images ofexternal objects are received. A healthy retina is soft,semitransparent, and has a purple tint. Upon exposure to ultravioletradiation it becomes clouded, opaque, and bleached. Prolonged exposureto ultraviolet radiation causes damage to the retina.

High-energy visible light (HEV light) is high-frequency light in theviolet/blue band in the visible spectrum, between 380 and 500 nm. HEVlight is thought to be a cause of age-related macular degenerationresulting from damage to the central portion of the retina. Although ithas not been conclusively shown to cause retinal damage, absorption ofHEV light has been shown to cause a reversal in the natural visualcycle, resulting in a greater potential for oxidative damage to the eye.Thus, the lens of the eye and the retina may show irreversible changesinduced by prolonged exposure to moderate levels of HEV light.Additionally, following an intraocular lens implant, the retina becomesparticularly sensitive to HEV light exposure.

A need exists for an ophthalmic solution that can be applied to the eyeto absorb ultraviolet radiation and to filter out HEV light.

BRIEF SUMMARY OF THE INVENTION

The present invention provides ophthalmic solutions and packagedophthalmic solutions for absorbing UV-A and UV-B radiation and filteringout HEV light. In addition, methods of absorbing ultraviolet radiation,such as UV-A and UV-B radiation, and filtering HEV light usingophthalmic solutions are provided.

In one aspect of the invention, an ophthalmic solution is provided. Inparticular, the ophthalmic solution comprises a UV-A absorber and a UV-Babsorber and has a viscosity of between about 1 and 100 cps. Theophthalmic solution may have a pH of between about 6.4 and 8.4.

In one embodiment, the UV-A absorber is avobenzone and the UV-B absorberis ethylhexyl methoxycinnamate.

In another embodiment, the viscosity of the ophthalmic solution isbetween about 4 and 12 cps. In another particular embodiment, theviscosity of the ophthalmic solution is about 8 cps.

In another aspect of the invention, the ophthalmic solution containshomosalate, an additional UV-A absorber.

In another aspect of the invention, the ophthalmic solution containsoctisalate, an additional UV-A absorber.

In another aspect of the invention, the ophthalmic solution containsoctocrylene, an additional UV-A absorber.

In another aspect of the invention, the ophthalmic solution containsoxybenzone, an additional UV-A absorber.

In another aspect of the invention, the ophthalmic solution containsensulizole, an additional UV-B absorber.

In another embodiment, the ophthalmic solution further comprises atleast one preservative, at least one surfactant, at least one bufferingagent to maintain a desired pH, a viscosity building agent, and at leastone emulsifier.

In an additional embodiment, an ophthalmic solution is provided. Theophthalmic solution comprises between about 0.05 and 0.6% by weightavobenzone; between about 0.05 and 0.6% by weight ethylhexylmethoxycinnamate; between about 1 and 5% by weight polysorbate 80;between about 1 and 5% by weight propylene glycol; between about 0.01and 0.1% by weight methyl paraben; and between about 0.009 and 0.1% byweight propyl paraben. The ophthalmic solution has a viscosity betweenabout 1 and 100 cps and a pH between about 6.4 and 8.4.

In another embodiment, the ophthalmic solution further comprises betweenabout 0.05 and 1% by weight of at least one adjuvant or additional UV-Aabsorber selected from the group consisting of homosalate, octisalate,octocrylene, and oxybenzone.

In an additional embodiment, the ophthalmic solution further comprisesbetween about 0.05 and 1% by weight ensulizole.

In another embodiment, the ophthalmic solution further comprises an HEVfilter. In a particular embodiment, the ophthalmic solution containsbetween about 0.01 and 2.66 μM riboflavin-5-sodium phosphate.

In another embodiment, a method of absorbing UV-A and UV-B radiationcontacting the eye is provided. The method comprises providing anophthalmic solution comprising an ultraviolet-A absorber and anultraviolet-B absorber, and applying the ophthalmic solution to an eye.The ophthalmic solution has a viscosity of between about 1 and 100 cps.A suitable viscosity building agent may be utilized. Suitable viscositybuilding agents can be selected from cetyl alcohol, polysorbate 80,propylene glycol and methyl cellulose, for example.

In a further embodiment, the ophthalmic solution also comprisesriboflavin-5-sodium phosphate. The riboflavin-5-sodium phosphateindicates when the ophthalmic solution needs to be reapplied to the eye.

In one particular embodiment, the UV-A absorber is avobenzone. Inanother particular embodiment, the UV-B absorber is ethylhexylmethoxycinnamate.

In a further embodiment, the ophthalmic solution further comprises atleast one additional UV-A absorber, selected from the group comprisinghomosalate, octisalate, octocrylene, and oxybenzone.

In another embodiment, the ophthalmic solution further comprises anadditional UV-B absorber, ensulizole.

In another particular embodiment, the ophthalmic solution has aviscosity of about 8 cps and a pH of between about 6.4 and 8.4.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to an aqueous dispersion of at leastone chromophore to form an ophthalmic solution to absorb UV-A and UV-Bradiation and filter out HEV light in the eye.

The ophthalmic solution of this invention can be used to absorb UV-A andUV-B radiation and filter out HEV light in the eye. The visible lightspectrum of light is around 400 nm and above. UV-A radiation has awavelength of between about 325 nm and 400 nm. UV-B radiation has awavelength of between about 290 nm and 325 nm.

A typical UV-A absorber for use in the ophthalmic solution of thepresent invention is avobenzone. Avobenzone has the molecular formula:

Avobenzone absorbs ultraviolet light over a wide range of wavelengths,absorbing up to a maximum of 357 nm.

The present invention typically contains a chromophore to absorb UV-Bradiation. A typical UV-B absorber for use in the ophthalmic solution ofthe present invention is ethylhexyl methoxycinnamate. Ethylhexylmethoxycinnamate has the molecular formula:

Ethylhexyl methoxycinnamate is an oil soluble, essentially colorless,and essentially odorless liquid. Ethylhexyl methoxycinnamate is aneffective UV-B absorber, and use of ethylhexyl methoxycinnamate in anophthalmic solution will absorb UV-B radiation, resulting in less UV-Bradiation reaching and affecting the cornea and retina.

The ophthalmic solution typically has a viscosity of between about 1 and100 cps. More typically, the ophthalmic solution has a viscosity ofbetween about 1 and 25 cps. More typically, the ophthalmic solution hasa viscosity of between about 4 and 12 cps. Most typically, theophthalmic solution has a viscosity of about 8 cps.

Optionally, a suitable viscosity building agent may be utilized.Suitable viscosity building agents can be selected from cetyl alcohol,polysorbate 80, propylene glycol and methyl cellulose, for example. Aviscosity building agent may not be needed to reach the desiredviscosity, but may be desired to maintain retention of the eye drop.

The present invention can contain any suitable chromophore to absorbultraviolet radiation. Examples of chromophores that can be used in theophthalmic solution include, but are not limited to, avobenzone,ethylhexyl methoxycinnamate, homosalate, octisalate, octocrylene,oxybenzone, and ensulizole. The ophthalmic solution may contain any ofthe listed chromophores in any combination, or may contain any suitablechromophore for instilling onto the human eye and that effectivelyabsorbs ultraviolet radiation. The chromophore may be present in anysuitable amount to absorb ultraviolet radiation when instilled onto theexterior surface of the human eye.

The ophthalmic solution can include homosalate. Homosalate absorbsultraviolet rays with a wavelength from about 295 nm to about 315 nm andhas the molecular formula:

The ophthalmic solution can also include octisalate. Octisalate absorbsultraviolet rays, particularly UV-B radiation, and has the molecularformula:

The ophthalmic solution can also include octocrylene. Octocryleneabsorbs ultraviolet rays with a wavelength between about 280 nm to about320 nm and has the molecular formula:

The ophthalmic solution can also include oxybenzone. Oxybenzone absorbsboth UV-A and UV-B radiation, with an absorption spectrum extending toless than about 350 nm. Oxybenzone is colorless crystals that readilydissolve in most organic solvents and has the molecular formula:

The ophthalmic solution can also include ensulizole. Ensulizole absorbsprimarily UV-B radiation, is water soluble, and has the molecularformula:

The ophthalmic solution can also include an HEV filter. Typically, ayellow dye is utilized as an HEV filter. Any ophthalmically appropriateyellow dye may be utilized. Typically, riboflavin, in the form ofriboflavin-5-sodium phosphate, is utilized as an HEV filter. The yellowdye also serves to indicate when it is necessary to reapply theophthalmic solution. Typically, the ophthalmic solution comprisesbetween about 0.01 and 2.66 μM riboflavin-5-sodium phosphate. Theophthalmic solution comprises between about 0.2 and 1.5 μMriboflavin-5-sodium phosphate.

Inactive ingredients in the ophthalmic solution include polysorbate 80,propylene glycol, methyl paraben, and propyl paraben. Any other inactiveingredients may be added as necessary.

The balance of the ophthalmic solution is purified water, and thesolution is adjusted to a pH of between about 6.4 and 8.4 using 0.1 NNaOH. Typically, the solution has a pH of about 7.4.

The ophthalmic solution is typically isotonic. The ophthalmic solutionis typically a micelle suspension.

Typically, the ophthalmic solution comprises between about 0.05% and 1%by weight avobenzone. The ophthalmic solution can comprise between about0.2% and 0.5% by weight avobenzone. Alternatively, the ophthalmicsolution can comprise between about 0.05% and 0.2% by weight avobenzone.In one specific embodiment, the ophthalmic solution comprises about 0.1%by weight avobenzone.

Typically, the ophthalmic solution comprises between about 0.05% and 1%by weight ethylhexyl methoxycinnamate. The ophthalmic solution cancomprise between about 0.2% and 0.5% by weight ethylhexylmethoxycinnamate. Alternatively, the ophthalmic solution can comprisebetween about 0.05% and 0.2% by weight ethylhexyl methoxycinnamate. Inone specific embodiment, the ophthalmic solution comprises about 0.1% byweight ethylhexyl methoxycinnamate.

The ophthalmic solution may comprise homosalate. Typically, theophthalmic solution comprises between about 0.05% and 1% by weighthomosalate. The ophthalmic solution can comprise between about 0.2% and0.5% by weight homosalate. Alternatively, the ophthalmic solution cancomprise between about 0.05% and 0.2% by weight homosalate. In onespecific embodiment, the ophthalmic solution comprises about 0.1% byweight homosalate.

The ophthalmic solution may comprise octisalate. Typically, theophthalmic solution comprises between about 0.05% and 1% by weightoctisalate. The ophthalmic solution can comprise between about 0.2% and0.5% by weight octisalate. Alternatively, the ophthalmic solution cancomprise between about 0.05% and 0.2% by weight octisalate. In onespecific embodiment, the ophthalmic solution comprises about 0.1% byweight octisalate.

The ophthalmic solution may comprise octocrylene. Typically, theophthalmic solution comprises between about 0.05% and 1% by weightoctocrylene. The ophthalmic solution can comprise between about 0.2% and0.5% by weight octocrylene. Alternatively, the ophthalmic solution cancomprise between about 0.05% and 0.2% by weight octocrylene. In onespecific embodiment, the ophthalmic solution comprises about 0.1% byweight octocrylene.

The ophthalmic solution may comprise oxybenzone. Typically, theophthalmic solution comprises between about 0.05% and 1% by weightoxybenzone. The ophthalmic solution can comprise between about 0.2% and0.5% by weight oxybenzone. Alternatively, the ophthalmic solution cancomprise between about 0.05% and 0.2% by weight oxybenzone. In onespecific embodiment, the ophthalmic solution comprises about 0.1% byweight oxybenzone.

The ophthalmic solution may comprise ensulizole. Typically, theophthalmic solution comprises between about 0.05% and 1% by weightensulizole. The ophthalmic solution can comprise between about 0.2% and0.5% by weight ensulizole. Alternatively, the ophthalmic solution cancomprise between about 0.05% and 0.2% by weight ensulizole. In onespecific embodiment, the ophthalmic solution comprises about 0.1% byweight ensulizole.

The ophthalmic solution of the invention may also include one or moresurfactant(s) and emulsifier(s). The surfactant(s) and emulsifier(s)function to maintain dispersion of the lipophilic components. Suitablesurfactants and emulsifiers may be selected from nonionic surfactants,cationic surfactants, polysorbates, hydroxypropyl methyl cellulose,benzalkonium chloride, and combinations thereof. Examples of nonionicsurfactants and emulsifiers include polysorbates such as polysorbate 80,glyceryl esters, polyoxyethylene glycol esters and ethers, and thesorbitan fatty acid esters and their polyoxyethylene derivatives.Polysorbate 80 is a nonionic surfactant and emulsifier that can formpart of the ophthalmic solution of the present invention. Typically, theophthalmic solution comprises between about 1% and 5% by weightpolysorbate 80. More typically, the ophthalmic solution comprisesbetween about 1% and 3% by weight polysorbate 80. Most typically, theophthalmic solution comprises about 2% by weight polysorbate 80.

Propylene glycol is a colorless and nearly odorless viscous liquid withmany different uses. Propylene glycol is utilized as a solvent inpharmaceuticals, as an emulsification agent, and as a moisturizer.Typically, the ophthalmic solution comprises between about 1% and 5% byweight propylene glycol. More typically, the ophthalmic solutioncomprises between about 1% and 3% by weight propylene glycol. Mosttypically, the ophthalmic solution comprises about 2% by weightpropylene glycol.

The ophthalmic solution may contain a variety of preservatives asappropriate to provide a stable solution and prohibit microbial andfungal growth. Preservatives are typically present when the ophthalmicsolution is packaged in multidose containers. A preservative is nottypically needed when the ophthalmic solution is packaged in a monodosecontainer. Examples of preservatives that can be found in the ophthalmicsolution include, but is not limited to, methyl paraben, propyl paraben,benzalkonium chloride, benzethonium chloride, cetyl pyridinium, benzylbromide, EDTA, phenylmercury nitrate, phenylmercury acetate, thimerosal,merthiolate, acetate and phenylmercury borate, polymyxin B sulphate,chlorhexidine, methyl and propyl parabens, phenylethyl alcohol,quaternary ammonium chloride, sodium benzoate, sodium propionate andsorbic acid. The ophthalmic solution may contain any effective amount ofa preservative or combination of preservatives necessary to provide astable solution and prohibit microbial and fungal growth.

Typically, the ophthalmic solution may contain methyl paraben and/orpropyl paraben in any effective amount for prohibiting microbial andfungal growth without detrimentally affecting the ophthalmic solution.The ophthalmic solution may also be stored in single-use vials which donot require the use of a preservative.

Methyl paraben is an antimicrobial and anti-fungal agent that isconsidered generally recognized as safe (GRAS) for food, pharmaceutical,and cosmetic antibacterial preservation. Typically, the ophthalmicsolution comprises between about 0.01% and 0.1% by weight methylparaben. More typically, the ophthalmic solution comprises between about0.025% and 0.075% by weight methyl paraben. Most typically, theophthalmic solution comprises about 0.05% by weight methyl paraben.

Propyl paraben is an antimicrobial and anti-fungal agent that isconsidered GRAS for food, pharmaceutical, and cosmetic antibacterialpreservation. Typically, the ophthalmic solution comprises between about0.001% and 0.1% by weight propyl paraben. More typically, the ophthalmicsolution comprises between about 0.009% and 0.075% by weight propylparaben. Most typically, the ophthalmic solution comprises about 0.01%by weight propyl paraben.

The ophthalmic solution typically has a viscosity of between about 1 and100 cps. The low viscosity of the ophthalmic solution allows thesolution to easily form a drop that can be applied directly into an eye.Typically, the ophthalmic solution has a viscosity between about 2 and25 cps. Typically, the ophthalmic solution has a viscosity between about4 and 12 cps. More typically, the ophthalmic solution has a viscosity ofabout 8 cps.

The ophthalmic solution typically has a pH of between about 6.4 and 8.4.Typically, the ophthalmic solution has a pH of between about 7.2 and7.6. Most typically, the ophthalmic solution has a pH of about 7.4.

An ophthalmic solution in accordance with the invention can be packagedin any suitable container known to those skilled in the art. Any type ofpackaging and packaging material that is suitable for storing theophthalmic solution of the invention may be utilized. Non-limitingexamples of packaging include bottles, ampules, pouches and envelopes.The packaging material generally should exhibit a high degree of oxygenand other gas impermeability. For that reason, pouches and envelopescould be made of a foil laminate material as is well known in the art.The packaging typically will be suitable for allowing the ophthalmicsolution to be instilled directly into the eye in a drop-wise fashion. Asqueeze bottle or an eye drop bottle may be utilized, for example.

The ophthalmic solution is topically administered to the eye or eye areaabout every three to six hours or as needed for protection from HEVlight and UV-A and UV-B radiation. Alternatively, the ophthalmicsolution is topically administered to the eye or eye area as often asindicated by a yellow visibility marker.

Another aspect of the present invention relates to a method of absorbingUV-A and UV-B radiation contacting the eye. The method of ultravioletradiation contacting the eye comprises topically administering to an eyean ophthalmic solution as described herein. An ophthalmic solution asdescribed herein is provided. The ophthalmic solution comprises an UV-Aabsorber and an UV-B absorber, wherein the ophthalmic solution has aviscosity of between about 1 and 100 cps. The ophthalmic solution mayhave a viscosity of between about 4 and 12 cps and a pH between about6.4 and 8.4. Typically, the ophthalmic solution comprises between about0.05% and 0.6% by weight avobenzone; between about 0.05% and 0.6% byweight ethylhexyl methoxycinnamate; between about 1% and 5% by weightpolysorbate 80; between about 1% and 5% by weight propylene glycol;between about 0.01% and 0.1% by weight methyl paraben; and between about0.001% and 0.1% by weight propyl paraben. The ophthalmic solution istopically administered to the eye.

The method may also filter HEV light. An ophthalmic solution asdescribed herein is provided. The ophthalmic solution includes an HEVfilter, such as riboflavin-5-sodium phosphate. Riboflavin-5-sodiumphosphate also serves as a yellow visibility marker. The yellowvisibility marker indicates when the ophthalmic solution needs to betopically reapplied to the eye.

The ophthalmic solution may also contain other ultraviolet absorbers,such as but not limited to, homosalate, octisalate, octocrylene,oxybenzone, and/or ensulizole.

EXAMPLES

The present invention is described in more detail with reference to thefollowing non-limiting examples, which are offered to more fullyillustrate the invention, but are not to be construed as limiting thescope thereof.

Example 1

An ophthalmic solution with the following formulation can be prepared:

TABLE 1 Compound Weight Percent (%) Avobenzone 0.1% Ethylhexylmethoxycinnamate 0.1% Polysorbate 80   2% Propylene glycol   2% Methylparaben 0.05%  Propyl paraben 0.01%  Purified water q.s. 0.1N NaOHAdjust to a pH of 7.4

Example 2

The ophthalmic solution of Example 1 can be topically administered to apatient to absorb UV-A and UV-B radiation in the eye. The ophthalmicsolution can be topically administered directly on the eye at leastdaily.

While the invention has been described with respect to certain preferredembodiments, as will be appreciated by those skilled in the art, it isto be understood that the invention is capable of numerous changes,modifications and rearrangements, and such changes, modifications andrearrangements are intended to be covered by the following claims.

What is claimed is:
 1. A method of absorbing ultraviolet-A and ultraviolet-B radiation contacting the eye comprising: applying an ophthalmic solution to an eye, the ophthalmic solution comprising an ultraviolet-A absorber selected from the group consisting of avobenzone, oxybenzone, and mixtures thereof and an ultraviolet-B absorber selected from the group consisting of ethylhexyl methoxycinnamate, homosalate, octisalate, octocrylene, ensulizole, and mixtures thereof, wherein the ophthalmic solution has a viscosity of between about 1 and 100 cps.
 2. The method of claim 1 wherein the ultraviolet-A absorber is avobenzone and the ultraviolet-B absorber is ethylhexyl methoxycinnamate.
 3. The method of claim 1 wherein the ophthalmic solution further comprises riboflavin-5-sodium phosphate, and wherein the riboflavin-5-sodium phosphate indicates when the ophthalmic solution needs to be reapplied to the eye.
 4. The method of claim 1 wherein the ophthalmic solution further comprises at least one ultraviolet absorber selected from the group comprising homosalate, octisalate, octocrylene, and oxybenzone.
 5. The method of claim 1 wherein the ophthalmic solution further comprises ensulizole.
 6. The method of claim 1 wherein the ophthalmic solution has a viscosity of between about 4 and 12 cps and a pH of between about 6.4 and 8.4.
 7. The method of claim 1 wherein the ophthalmic solution further comprises an HEV filter, the composition capable of absorbing high-energy visible light when applied to a person's eye.
 8. The method of claim 7 wherein the HEV filter is riboflavin-5-sodium phosphate.
 9. The method of claim 1 wherein the ophthalmic solution consists essentially of the ultraviolet-A absorber, the ultraviolet-B absorber, at least one preservative, at least one surfactant or emulsifier, at least one buffering agent, a viscosity building agent, an HEV filter compound, and at least one additional chromophore for absorbing ultraviolet radiation.
 10. The method of claim 1 further comprising providing the ophthalmic solution.
 11. A method of absorbing ultraviolet-A and ultraviolet-B radiation contacting the eye comprising: applying an ophthalmic solution to an eye, the ophthalmic solution comprising avobenzone in an amount between about 0.05% and 0.6% by weight of the ophthalmic solution; between about 0.05% and 0.6% by weight ethylhexyl methoxycinnamate; between about 1% and 5% by weight polysorbate 80; between about 1% and 5% by weight propylene glycol; between about 0.01% and 0.1% by weight methyl paraben; and between about 0.009% and 0.1% by weight propyl paraben.
 12. The method of claim 11 wherein the ophthalmic solution further comprises between about 0.05% and 1% by weight of at least one ultraviolet absorber selected from the group consisting of homosalate, octisalate, octocrylene, and oxybenzone; and between about 0.05% and 1% by weight ensulizole.
 13. The method of claim 11 wherein the ophthalmic solution further comprises between about 0.01 and 2.66 μM riboflavin-5-sodium phosphate.
 14. The method of claim 11 wherein the ophthalmic solution consists essentially of the avobenzone, the methoxycinnamate, the polysorbate 80, propylene glycol, methyl paraben, propyl paraben, an HEV filter compound and optionally at least one buffering agent.
 15. The method of claim 11 further comprising providing the ophthalmic solution. 